Innate Lymphoid Cell Aging

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Project Summary/Abstract Under this administrative supplement, we propose to examine impact of innate lymphoid cell aging on the disease outcome of SARS-CoV-2 infection, by adding COVID-19 to the parent study which examines the innate lymphoid cell aging during influenza infection. The aged population is particularly susceptible to COVID-19. It is estimated that more than 80% of individuals who have died from COVID-19 in the U.S. are elderly individuals ≥ 65 years old. The underlying mechanisms remain unclear. Aging is associated drastic and complicated changes in the immune system. Aging is associated drastic and complicated changes in the immune system. The mucosal barrier sites harbor unique subsets of innate and innate-like lymphocytes implicated in host defense, tissue homeostasis, and tissue repair. Our published and preliminary data indicate that the long-lived lung-resident innate/innate-like lymphocytes, such as ILC2 and MAIT cells, undergo tremendous changes with aging. We hypothesize that impaired function of mature lung ILC2 underpins tissue damage and inflammation observed during SARS-CoV-2 infection with aging, and that boosting the activity of ILC2 will increase host resistance and tolerance to severe COVID-19 in the elderly individuals. We have recently established a mouse model of SARS-CoV-2 infection in aged mice. We will further characterize this mouse model, and will use this model to test whether enhancing ILC2 activity will increase host resistance and tolerance resistance to COVID-19 in aged mice. We have available for this study a CDC approved full functioning ABSL3 lab. This supplement will directly address multiple objectives related to the goals outlined in the COVID-19 notice of special interest. This supplement will develop aged animal models suitable for studies on pathogenesis of SARS-CoV-2 infection in the aging context. The proposal experiments will also elucidate how cellular and molecular mechanisms of aging impact the treatment, recovery, and repair of tissue and organ systems during SARS-CoV-2 infection.